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CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease
Kylie A. Alexander, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Kylie A. Alexander, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Published October 1, 2014; First published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4266-4280. https://doi.org/10.1172/JCI75935.
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Categories: Research Article Immunology

CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease

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Abstract

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17–dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS–). Cutaneous cGVHD developed in a CSF-1/CSF-1R–dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r–/– mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti–CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD.

Authors

Kylie A. Alexander, Ryan Flynn, Katie E. Lineburg, Rachel D. Kuns, Bianca E. Teal, Stuart D. Olver, Mary Lor, Neil C. Raffelt, Motoko Koyama, Lucie Leveque, Laetitia Le Texier, Michelle Melino, Kate A. Markey, Antiopi Varelias, Christian Engwerda, Jonathan S. Serody, Baptiste Janela, Florent Ginhoux, Andrew D. Clouston, Bruce R. Blazar, Geoffrey R. Hill, Kelli P.A. MacDonald

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Figure 1

F4/80+ macrophages infiltrate the skin of mice receiving either mobilized or nonmobilized grafts.

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F4/80+ macrophages infiltrate the skin of mice receiving either mobilize...
(A–H) IHC to detect F4/80 expression in recipients of mobilized and nonmobilized grafts. Representative images of skin from lethally irradiated B6 mice that received G-CSF–mobilized BALB/c grafts. IHC was performed on days 7 (A), 14 (B), and 21 (C) after transplantation (n = 3/time point). F4/80+ macrophages were present in the dermis by day 7 after transplantation (A), with robust infiltration throughout the dermis at day 14 (B) and subcutaneous fat from day 21 (C). (D) Minimal F4/80+ macrophage infiltrate was noted in the skin of mice that received TCD grafts. (E–H) Representative images of F4/80 IHC in lethally irradiated B6D2F1 mice that received B6 BM plus T cell grafts. Skin was examined on days 21 (E) , 28 (F), and 35 (G) after transplantation (n = 3/time point). F4/80+ macrophage infiltrate was present in the dermis from day 21 after transplantation (E) and throughout the subcutaneous fat layer by day 28 (F and G). There was minimal F4/80+ macrophage infiltrate in mice that received TCD grafts (H). Original magnification, ×5.
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